As part of its ongoing efforts to make clinical trials more representative of the population, the FDA last week issued a final guidance on what sponsors should do to make trials more accessible and appealing to under-represented racial, ethnic, gender and age groups.

It’s an issue that has been increasingly on the front burner for industry stakeholders the past few years, and the COVID-19 pandemic has made the situation even more urgent as minority groups have proven more susceptible to the virus.

Clearly, the FDA agrees with industry that measures must be taken to increase the participation of underserved populations. While many of the recommendations the agency details in this new guidance are not new ideas, this is the first time the FDA has laid them out in a final guidance for the industry, giving trial sponsors and sites confidence that they have regulatory support for efforts to expand trial inclusion.

“Many of the recommendations have been introduced and discussed elsewhere,” says Tufts Center for the Study of Drug Development (CSDD) Deputy Director Ken Getz. “Still, the FDA’s guidance signals the agency’s desire to be part of the solution; to encourage and collaborate with clinical research sponsors in improving participant demographic subgroup representation.”

Recommendations in the new guidance focus on increasing diversity by loosening trial eligibility criteria, reducing barriers to trial participation, and increasing community and patient outreach.

The agency is right to point out these ideas from the regulatory perspective, says Steve Smith, WCG Clinical’s president of patient advocacy. The guidance is the latest in the FDA’s efforts over the past decade to promote trial diversity. “It’s not letting its foot off the gas,” Smith says.

The final version of the guidance, which was released in draft form in June 2019 and drew 90 public comments, includes three new suggestions for increasing trial inclusiveness: using real-world data, such as insurance claims and electronic health records, to identify appropriately diverse populations; using online/social media recruitment strategies to reach participants who don’t have access to a traditional referral center; and using electronic informed consent to allow participants to read and sign forms remotely.

In acknowledgement of practices that have proven useful during the COVID-19 pandemic, the guidance encourages trials to reduce barriers to trial participation by modifying study visit schedules or reducing the frequency of visits, using electronic communication or digital health technology and using mobile medical professionals, such as nurses and phlebotomists, to provide trial services locally.

Community and patient outreach efforts could include incorporating advocacy groups, medical associations and other stakeholders in trial design; and fostering community engagement through focus groups, community advisory boards and community-based research. 

The agency recommends reimbursing trial participants for expenses, such as for travel and lodging. Payment for participating in research may be allowed at the discretion of the trial’s IRB, such as for the participant’s time, inconvenience or discomfort. 

These and other measures can help the industry move beyond some common roadblocks, which, according to the Association of Clinical Research Professionals, include lack of awareness, logistics, mistrust, lack of diversity among the research and clinical professionals, research not being conducted in the community, disconnect between researchers and the community, limited access to specialty centers that refer patients to clinical trials, minorities not being as willing to participate in research, and fear of exploitation in clinical research.

A recent study from the CSDD found that clinical trial participation among Blacks and African Americans — who make up 13.4 percent of the U.S. population — was only 5.4 percent between 2007 and 2017 (CenterWatch Weekly, Nov. 2). And statistics from the FDA’s recently released 2015-2019 Drug Trials Snapshots Report show that Blacks/African Americans made up only 7 percent of participants in FDA-regulated trials in the five-year period examined. 

Although 18 percent of the U.S. population identifies as Latinx, that group represented only 7.2 percent of trial participants in the CSDD study. The group fared better in the FDA report, however, which showed it accounted for 13 percent of participants from 2015 to 2019.

To broaden trials, the guidance says, sponsors should eliminate or modify eligibility criteria that unnecessarily exclude specific populations, such as patients with organ dysfunction, comorbid conditions and disabilities. Sponsors that usually use the same criteria for phase 2 and phase 3 studies, the FDA says, could consider relaxing the restrictive criteria used in phase 2 studies, opening the door to more inclusive phase 3 criteria. 

Other recommendations include using adaptive trial designs that allow for the expansion of the participant pool as the trial proceeds; characterizing drug metabolism in certain populations early in the clinical development process; and considering broader inclusion of pediatric arms early in trial planning.

The guidance also addresses recruitment challenges of rare disease trials, suggesting sponsors increase their participant pools through such efforts as re-enrolling early-phase trial participants into later-phase randomized trials.  Sponsors could make rare-disease trials more attractive by establishing extension studies that guarantee the investigational treatment will be made available to all participants, including those who may have received a placebo in the main trial. 

The rare disease community is also an underserved population, Smith points out, saying that before the implementation of the Orphan Drug Act in 1983, it was in the same position minority groups are now. The rare disease community has been telling the FDA for two decades that more inclusive trial criteria are needed, he says, and the effort is paying off. “It’s called regulatory flexibility, and they’re getting it,” he says.

The guidance also refers to diversity by age of participant, focusing primarily on involvement of children in nonpediatric studies, but representation of the elderly in trials outside of geriatric studies also is an issue. The agency’s snapshots report shows than only one-third of trials included participants over age 65. Many of the same barriers that block minority participation also affect older populations, the guidance says, such as access to transportation. And comorbidities in older adults could lead to their exclusion from some trials.

In general, there are no major points of controversy in the guidance, says Angela Branche, assistant professor at the University of Rochester Medical Center, but no real innovations either. “I don’t think it adds much to what has already been pretty well understood,” Branche says.

“It’s important that this guidance be specific in detailing that a particular group should not have to endure a higher proportion of the risk,” she says.

Smith agrees that there is always more that can be done. But the responsibility isn’t all on the agency’s shoulders, he points out. Increasing trial diversity requires a collaboration among the FDA, the industry, patients and biostatisticians.

Read the final guidance here: https://bit.ly/2UvxSY5.